Diabetic autonomic neuropathy is an important clinical problem resulting in a significant increase in the morbidity and mortality of diabetes. In order to approach the pathogenesis and therapy of human diabetic autonomic neuropathy we have developed and characterized a neuropathologic model of experimental diabetic autonomic neuropathy in streptozotocin-induced diabetic rats. In previous studies degenerating, regenerating and dystrophic unmyelinated axons have been found: 1) in mesenteric nerves serving the distal small bowel and 2) in the prevertebral sympathetic ganglia innervating the alimentary tract. Dystrophic axons in mesenteric nerves represent populations of noradrenergic unmyelinated axons selectively innervating intramural myenteric ganglia in the small bowel. Subpopulations of presynaptic nerve endings in prevertebral but not paravertebral sympathetic ganglia also become dystrophic. The studies proposed in this research plan will investigate presynaptic neuroaxonal dystrophy in the superior mesenteric ganglia of STZ-diabetic rats: will determine its response to pancreatic islet, insulin, myo-inositol and aldose reductase inhibitor therapy, both preventive and after the development of structural lesions; will determine the origin of the dystrophic axons and their immunohistochemistry; and will quantitate peptidergic input with radioimmunoassay. Other studies will isolate the population of noradrenergic axons which eventually become dystrophic from the background perivascular noradrenergic population which do not become dystrophic by using neonatal guanethidine administration in rats. We will test two possible mechanisms of pathogenesis of diabetic autonomic neuropathy by examining: 1) if axonal regeneration induced with known mechanical and biochemical insults is frustrated or incomplete in diabetic animals, or 2) if early alteration sin the axonal transport of labeled proteins and glycoproteins in ileal mesenteric nerves are demonstrated. Finally, we will continue to examine the autonomic nervous system of aged or diabetic humans at autopsy to determine if the rat model faithfully mimics human diabetic autonomic neuropathy as our preliminary results suggest.